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Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment.

ABSTRACT: In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19-, A6- and ?-fetoprotein-positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.

SUBMITTER: Mu X

PROVIDER: S-EPMC4607132 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment.

Mu Xueru X Español-Suñer Regina R Mederacke Ingmar I Affò Silvia S Manco Rita R Sempoux Christine C Lemaigre Frédéric P FP Adili Arlind A Yuan Detian D Weber Achim A Unger Kristian K Heikenwälder Mathias M Leclercq Isabelle A IA Schwabe Robert F RF

The Journal of clinical investigation 20150908 10

In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a w ...[more]

PMID: 26348897

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Project description:UNLABELLED:Human hepatocellular carcinoma (HCC) is a heterogeneous disease of distinct clinical subgroups. A principal source of tumor heterogeneity may be cell type of origin, which in liver includes hepatocyte or adult stem/progenitor cells. To address this issue, we investigated the molecular mechanisms underlying the fate of the enzyme-altered preneoplastic lesions in the resistant hepatocyte (RH) model. Sixty samples classified as focal lesions, adenoma, and early and advanced HCCs were microdissected after morphological and immunohistochemical evaluation and subjected to global gene expression profiling. The analysis of progression of the persistent glutathione S-transferase (GSTP)(+) focal lesions to fully developed HCC showed that approximately 50% of persistent nodules and all HCCs expressed cytokeratin 19 (CK19), whereas 14% of remodeling nodules were CK19(+). Unsupervised hierarchical clustering of the expression profiles also grouped the samples according to CK19 expression. Furthermore, supervised analysis using the differentially expressed genes in each cluster combined with gene connectivity tools identified 1308 unique genes and a predominance of the AP-1/JUN network in the CK19(+) lesions. In contrast, the CK19-negative cluster exhibited only limited molecular changes (156 differentially expressed genes versus normal liver) consistent with remodeling toward differentiated phenotype. Finally, comparative functional genomics showed a stringent clustering of CK19(+) early lesions and advanced HCCs with human HCCs characterized by poor prognosis. Furthermore, the CK19-associated gene expression signature accurately predicted patient survival (P < 0.009) and tumor recurrence (P < 0.006). CONCLUSION:Our data establish CK19 as a prognostic marker of early neoplastic lesions and strongly suggest the progenitor derivation of HCC in the rat RH model. The capacity of CK19-associated gene signatures to stratify HCC patients according to clinical prognosis indicates the usefulness of the RH model for studies of stem/progenitor-derived HCC.

Project description:The cellular microenvironment plays a critical role in cell differentiation, proliferation, migration, and homeostasis. Recent studies have shown the importance of substrate viscosity in determining cellular function. Here, we study the mechanoresponse of normal hepatocytes and hepatocellular carcinoma cells (HCC) to elastic and viscoelastic substrates using the Huh7 cell line derived from a human liver tumor and primary human hepatocytes (PHH). Unlike PHH and fibroblasts, which respond to viscoelastic substrates by reducing spreading area and actin bundle assembly compared to purely elastic substrates of the same stiffness, Huh7 cells spread faster on viscoelastic substrates than on purely elastic substrates. The steady state spreading areas of Huh7 cells are larger on viscoelastic substrates, whereas the opposite effect occurs with PHH cells. The viscoelasticity of the microenvironment also promotes motility and multiple long protrusions in Huh7 cells. Pharmacologic disruption of the actin assembly makes cells unable to spread on either elastic or viscoelastic substrates. In contrast, upon vimentin perturbation, cells still spread to a limited degree on elastic substrates but are unable to spread on viscoelastic substrates. The time evolution of cell traction force shows that the peak occurs at an earlier time point on viscoelastic substrates compared to elastic substrates. However, the total force generation at steady state is the same on both substrates after 4 hours. Our data suggest that stress relaxation time scales of the viscoelastic substrate regulate cell dynamics and traction force generation, indicating different binding-unbinding rates of the proteins that form cell attachment sites in HCC cells and normal hepatocytes. These results suggest that liver cancer cells may have different characteristic lifetimes of binding to the substrate in comparision to normal cells, which might cause differences in cell spreading and motility within the diseased tissue.

Dataset Information

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment.

Publications

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment.

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